Sensipar® (cinacalcet) is a calcimimetic agent that has the chemical name N-[1-(R)-(−)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-aminopropane hydrochloride, has the empirical formula C22H22F3N.HCl and the structural formula shown in FIG. 5. The molecular weight of the hydrochloride salt is 393.9 g/mol and the free base is 357.4 g/mol. There is one chiral center in the molecule, and the R enantiomer is the more potent enantiomer.
Cinacalcet hydrochloride is commercially available as Sensipar® or Mimpara®. The calcimimetic agent is used to increase the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. This calcimimetic has been shown to be therapeutically effective in the treatment of patients with chronic kidney disease on dialysis that have secondary hyperparathyroidism and of hypercalcemia in patients with parathyroid carcinoma. Today there are more than 300,000 kidney dialysis patients with chronic kidney disease (CKD) in the U.S. alone. Nearly all of these patients suffer from secondary hyperparathyroidism (HPT), which is a progressive disease, associated with increases in parathyroid hormone (PTH) levels and abnormal calcium and phosphorus metabolism. In a typical patient having mild HPT, the iPTH levels are 300 to 500 pg/ml; a patient having moderate HPT has an iPTH of 500 to 800 pg/ml; and a patient with severe HPT has an iPTH of greater than 800 pg/ml. A normal iPTH level should be in the range of about 250 pg/ml. The lower limit of normal calcium level in humans is about 8.4 mg/dL. HPT can develop early during the course of CKD and continues to progress as kidney function declines. Untreated secondary HPT is characterized by abnormal calcium and phosphorus levels and is associated with serious consequences, including cardiovascular morbidity.
Increased PTH stimulates osteoclastic activity resulting in cortical bone resorption and marrow fibrosis. Sensipar® is the first treatment that meets a significant medical need in patients with secondary HPT to lower the levels of PTH, calcium, and phosphorus in the blood, in order to prevent progressive bone disease and the systemic consequences of disordered mineral metabolism. Reduction of PTH levels in CKD patients on dialysis with uncontrolled secondary HPT has been shown to have positive effects on bone-specific alkaline phosphatase (BALP), bone turnover and bone fibrosis.
PTH secretion is regulated through the action of a calcium-sensing receptor on the cell surface of the parathyroid gland. Sensipar® directly lowers PTH levels by increasing the sensitivity of this calcium-sensing receptor to extracellular calcium. The reduction in PTH is associated with a concomitant decrease in serum calcium levels.
Sensipar® is the only available therapy that allows practitioners to reduce PTH while lowering calcium-phosphorus product, which is consistent with the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (K/DOQI) clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Prior to its development, the only available medical treatments for patients with secondary HPT were phosphate binders and vitamin D sterols, which may elevate calcium and/or phosphorus levels. Such elevation would frequently require treatment to be interrupted and lead to an inadequate control of PTH.
It is now well-accepted that Sensipar® provides an excellent targeted treatment of secondary HPT with its unique mechanism of action that acts directly on the calcium-sensing receptor. Sensipar® provides significant improvement over traditional therapy to provide an important new tool to help dialysis patients suffering from secondary HPT. It also is successful in lowering calcium levels in patients with hypercalcemia due to parathyroid carcinoma. Patients with parathyroid carcinoma have a rare, serious cancer of the parathyroid gland results in excess secretion of PTH. Thus, parathyroid carcinoma is one form of primary HPT. The disease is complicated by elevated calcium levels in the blood. High calcium levels can lead to anxiety, depression, nausea, vomiting, bone fractures, kidney stones and in some cases coma. Surgical removal of the parathyroid gland is the only curative therapy for this disease but is not successful in all cases. Sensipar® was shown to reduce high levels of calcium in patients with parathyroid carcinoma.